Acta Psychiatr Scand 2014: 130: 40–45 All rights reserved DOI: 10.1111/acps.12231
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA PSYCHIATRICA SCANDINAVICA
Do patients with paranoid and disorganized schizophrenia respond differently to antipsychotic drugs? Corves C, Engel RR, Davis J, Leucht S. Do patients with paranoid and disorganized schizophrenia respond differently to antipsychotic drugs? Objective: The aim of this study was to compare the differential response to amisulpride in patients with paranoid versus disorganized schizophrenia. Method: We reanalyzed the original data from five different randomized drug trials comparing Brief Psychiatric Rating Scale (BPRS) scores in a database containing 427 paranoid and 296 disorganized patients with schizophrenia. Results: Both the disorganized and the paranoid group showed a substantial improvement of the BPRS total score within the first 4 weeks. In the paranoid group, mean (SD) BPRS reduction was 16.9 (14.6) (t = 24.06, df = 426, P < 0.001) and in the disorganized group 17.0 (15.9) (t = 18.49, df = 295, P < 0.001). An analysis of covariance (ANCOVA) controlling for BPRS at baseline and the influence of different trial protocols showed significant differences between diagnostic groups (F = 13.47, df = 1, P < 0.001), Cohen’s D 0.31 (CI = 0.16–0.46). Paranoid patients improved by 4.8 BPRS points more than disorganized patients (adjusted means 18.90 (CI = 17.33–20.37) for the paranoid and 14.1 (CI = 12.04 – 16.11) for the disorganized group. Conclusion: We conclude that amisulpride is effective in disorganized as well as in paranoid schizophrenia, but that symptom reduction in the disorganized subtype is less pronounced.
C. Corves1,2, R. R. Engel2,
J. Davis3, S. Leucht1
1 Department of Psychiatry and Psychotherapy, Technische Universit€at M€unchen, Munich, 2 Psychiatrische Klinik und Poliklinik, Klinikum der LMU, Munich, Germany and 3Psychiatric Institute, University of Illinois at Chicago, Chicago, IL, USA
Key words: schizophrenia; disorganized; paranoid; amisulpride; efficacy Stefan Leucht, Department of Psychiatry and Psychotherapy, Technische Universit€at M€unchen, Klinikum Rechts der Isar, Ismaningerstr. 22, 81675 Munich, Germany. E-mail: [email protected]
Accepted for publication November 6, 2013
Significant outcomes
• This •
is the first study that examines the effects of an antipsychotic in patients with paranoid vs. disorganized schizophrenia. The improvement was significantly greater in the paranoid group, when severity of illness at baseline was taken into account.
Limitations
• Diagnoses of schizophrenia subtype were not validated by SCID (Structured Clinical Interview for •
DSM) or M.I.N.I. (Mini-International Neuropsychiatric Interview), but were made based on a structured clinical interview according to the Diagnostic and Statistical Manual for Mental Disorders. There was no placebo group, but the symptom reduction was so large that it is unlikely to be simply due to the natural course.
Introduction
Antipsychotic medication is the standard treatment for patients with schizophrenia, and their success in reducing symptoms has been extensively 40
studied (1). Given the well-documented general efficacy of antipsychotics (2), it is surprising that there are no systematic studies of their efficacy on different schizophrenia subtypes, even though these may differ substantially in symptomatology.
Amisulpride in paranoid versus disorganized patients While according to ICD-10 (3) and DSM-IV (4) the undifferentiated type is by definition a mixed form and the residual subtype is characterized mainly by residing symptoms of low severity, the paranoid, the disorganized (termed hebephrenic in ICD-10), and the catatonic subtype differ substantially in symptoms (3, 4). It is unclear how well patients with different subdiagnoses respond to antipsychotics, because subgroups are generally combined in analyses of randomized controlled trials. In a MEDLINE search (Medical subject headings search terms: schizophrenia, hebephrenia, disorganized, catatonia, subtype/subcategory, date: 1966–2013), we did not find any primary or post hoc analyses on the different subgroups [also see (5)]. One reason for this may be that analyses of subgroups would usually be underpowered, as the sample size estimations of single trials are made for pooled analyses. Although the subtypes are defined based on convention and only partly on empirical evidence and might not reflect etiologically and neurobiological distinct pathologies, it is common clinical practice to differentiate them. DSM-5 has abandoned the schizophrenia subtypes (6), and experts working on ICD-11 need to make a decision whether they want to follow this path. It is therefore crucial to know whether these subdiagnoses have implications for treatment efficacy. Aims of the study
The aim of this study was to provide an analysis comparing the efficacy of a second-generation
antipsychotic drug on paranoid and disorganized schizophrenia in a pooled database of registrational amisulpride studies in acute schizophrenia. As described above, symptoms between the disorganized subtype and the paranoid subtype differ but overlap. As efficacy has already been demonstrated for the paranoid subtype, we would expect patients with disorganized schizophrenia to respond to treatment. This should be reflected in a significant reduction in symptom severity as compared with baseline in the disorganized group.
Material and methods Sample
We post hoc reanalyzed data from five trials on amisulpride comprising patients diagnosed with disorganized as well as paranoid schizophrenia [Colonna et al. (7); M€ oller et al. (8); Peuskens et al. (9); Puech et al. (10); Sechter et al. (11)], see Table 1. Two other amisulpride trials were available [Carriere et al. (12); Wetzel et al. (13)] but did not include a single patient of the disorganized subtype and were therefore disregarded. All studies were randomized, and apart from one open study (7), all were double blind and used a parallel design. The studies were mainly conducted for registrational purposes and compared amisulpride with either haloperidol (7, 8, 10) or with risperidone (9, 11). Study duration ranged between 4 weeks and 1 year (7). Two studies (7, 11) used a flexible-dose
Table 1. Characteristics of the included studies Dose (mg/day) of amisulpride
Study
n
par
dis
M€oller et al. (8)
75
32
43
6
800*
Puech et al. (10)
139
48
91
4
100‡, 400, 800 or 1200
Colonna et al. (7)
280
160
120
51
Peuskens et al. (9)
97
71
26
8
Sechter et al. (11)
132
116
16
26
Weeks
200–1200 (flexible dose, mean 614) 800
400–1000 (flexible dose, mean 655)
Selected patient characteristics In-patients with paranoid, disorganized, or undifferentiated schizophrenia, DSM-III-R, BPRS psychotic subscore† ≥12 and at least two BPRS psychosis items ≥4 In-patients with acute exacerbations of paranoid, disorganized, or undifferentiated schizophrenia, DSM-III-R, BPRS psychotic subscore ≥12 and at least two BPRS psychosis items ≥4 In- or out-patients with acute exacerbations of paranoid, disorganized, or undifferentiated schizophrenia, DSM-III-R, at least two BPRS psychosis items ≥4 In- or out-patients with paranoid, disorganized or undifferentiated schizophrenia, DSM-IV, BPRS total score ≥36, BPRS psychotic subscore ≥12 and at least two BPRS psychosis items ≥4 In- or outpatients with chronic (at least 2 years) paranoid, disorganized, undifferentiated, or residual schizophrenia, DSM-IV, PANSS ≥60 ≤ 120, 0.05). Results of univariate analyses
Unpaired t-tests and chi-square tests showed statistically significant differences between groups for trial [v2(4) = 96.7, P < 0.001] and BPRS at baseline (t = 9.85, df = 721, P < 0.001), with a mean of 53.8 (10.7) in the paranoid group compared with 61.8 (10.9) in the disorganized group. There was no significant difference in terms of gender (P = 0.53), duration of illness below or above 2 years (P = 0.23), duration of illness in days (P = 0.86), age (P = 0.07), or amisulpride dose (P = 0.15). Comparison of subtypes Week four
The ANCOVA yielded significant main effects for subtype (F = 13.47, df = 1, P < 0.001), demon-
Amisulpride in paranoid versus disorganized patients strating a significant difference between groups and a greater symptom reduction in the paranoid (adjusted means 18.9 (CI = 17.3–20.4) than in the disorganized group 14.1 (CI = 12.0–16.1), Cohen’s D 0.31 (CI = 0.16–0.46). In addition, the ANCOVA yielded significant effects on baseline severity (F = 122.13, df = 1, P < 0.001) and trial (F = 7.38, df = 4, P < 0.001). The interaction between subtype and trial was not significant. Study endpoint
This ANCOVA showed a similar pattern. There was a main effect for subtype [F = 8.30, df = 1, P < 0.005, Cohen’s d = 0.25 (CI = 0.11–0.40)], with estimated adjusted mean BPRS reduction of 20.3 (CI = 18.6–22.0) in the paranoid and 16.1 (CI = 13.8–18.4) in the disorganized group. Again, there were significant effects of severity at baseline (F = 115.54, df = 1, P < 0.001), but not of trial (f = 2.02, df = 4, P = 0.90). The interaction between subtype and trial was not significant. Correlation of symptom reduction and baseline severity
There was an obvious discrepancy between the virtually identical mean raw symptom reduction in both groups [16.9 BPRS points (14.6) in the paranoid group and 17.0 (15.9) in the disorganized group, difference non-significant] and the ANCOVA results (significant difference (F = 13.47, df = 1, P < 0.001) between paranoid [adjusted means 18.90 (CI = 17.33–20.37) and the disorganized group 14.1 (CI = 12.0–16.1), Cohen’s D 0.31 (CI = 0.16–0.46), as described above]. To find out whether this was associated with the significantly higher baseline severity in the disorganized group (see above), we correlated baseline severity with symptom reduction and found a positive correlation (N = 723, r = 0.38, P < 0.001). As the disorganized group had a higher degree of severity at baseline (see above), this suggests that the stronger reduction in symptoms in the paranoid group was not an artifact of unequal baseline scores. Discussion
The main results of this study are as follows both the paranoid and the disorganized subgroup experienced a robust reduction in symptoms. However, the reduction in symptoms was larger in the paranoid group as is indicated by an ANCOVA, taking trial and baseline differences into account. Generally, a higher degree of severity at baseline was associated with significantly greater symptom reduction, but although the disorganized partici-
pants were significantly more ill at baseline, they did not show higher reduction scores. The efficacy of antipsychotic drugs for the different subgroups of schizophrenia has been studied surprisingly little. There are very few randomized controlled trials that examined subgroups of patients with schizoaffective disorder [a review by Baethge (2003) (19) found only one], a heterogeneous disorder (20) that is considered to be a different diagnostic group rather than a schizophrenia subtype. Other studies analyzed the effects of medication on empirically derived symptom clusters: Marder et al. (21), for instance, derived symptom dimensions using factor analyses and found that risperidone’s superiority over haloperidol was significantly greater for some dimensions (negative symptoms, hostility/excitement, anxiety/depression) than for others (positive symptoms, disorganized thought), suggesting that risperidone and other serotonin/dopamine antagonists are in effect qualitatively different from haloperidol. An analysis of pivotal olanzapine studies (22) identified different symptom dimensions by factor analyses and found that olanzapine was better than haloperidol to an equal degree in all of them. These studies were quite different from ours, because they examined differences in subgroups of symptoms not patients. None of them examined the effects on the DSM/ICD defined subgroups of schizophrenia, which is crucial information for the clinician. The 4.8-point difference in BPRS total score found in the ANCOVA is relatively small as it corresponds to a 0.5-point difference on the CGI where 1 point reflects minimal improvement. On the other hand, a meta-analysis (38 studies, n = 7323) found an only nine BPRS points difference between second-generation antipsychotics and placebo (2). The 4.8 points difference also appears larger in the light of a review by Lepping et al., 2011 (23), which found that second-generation antipsychotics reduced the BPRS baseline score by 15.0 7.2 points. Various limitations must be considered: First, our data set consisted in a mix of fixeddose and flexible-dose studies. Generally, a fixeddose design could be associated with a less favorable outcome, as patients do not necessarily obtain the optimal dose balancing symptom reduction and adverse effects. Consequently, dropout rates may be higher and symptom reduction lower. It has been argued that flexible-dose studies better approximate clinical practice and therefore also the treatment benefit that can be expected in a clinical setting (24). Conversely, it is an advantage of the fixed-dose studies in our database that they 43
Corves et al. kept the factor dose constant, which could have interacted with the schizophrenia subtype. Second, the diagnosis of the participants in the included RCTs were not validated by Structured Clinical Interview for DSM (SCID) (25) or Mini-International Neuropsychiatric Interview (M.I.N.I)(26), but with a structured clinical interview according to DSM-III-R(IV). On the other hand, there is no reason to assume that the accuracy of diagnosis is particularly low in these studies as in general practice diagnosis is also made in the absence of a SCID. Third, only a placebo group could prove that amisulpride is efficacious for both paranoid and disorganized patients. But the BPRS reduction from baseline was so large (17 points) that this should not be a major concern. For example, in the review by Lepping et al., 2011 placebo reduced the BPRS by 2.3 3.7 points in similar studies. Fourth, the current analysis compared only disorganized and paranoid schizophrenia, but not catatonic schizophrenia. However, this subtype is very rare in clinical trials [only 1.7% in our database, also see, e.g., (27)], and it has been repeatedly argued that catatonia constitutes a distinct syndrome separate from schizophrenia (28–30). In DSM-5, the strong relation to schizophrenia has been loosened together with the deletion of the subtypes. Although not a separate diagnosis, catatonia is included as a specifier, which can be applied not only to schizophrenia but also to several other psychiatric diagnoses. Finally, an important limitation of this study is its focus on amisulpride. Other antipsychotic agents than amisulpride need to be examined to enhance generalizability. Currently, the question to what extent the difference in response between the two diagnostic groups depends on a specific antipsychotic agent remains to be examined. In conclusion, this study demonstrates that amisulpride is effective for patients diagnosed with paranoid and disorganized schizophrenia, but it also suggests that the effects on the paranoid subtype are stronger. These results have an impact on the decision whether ICD-11 should follow the abolishment of diagnostic subcategories of schizophrenia by DSM-5(6). Acknowledgements We would like to thank SanofiAventis for providing the raw data of the original studies.
Declaration of interest Stefan Leucht has received honoraria for consulting/advisory boards from Alkermes, BristolMyersSquibb, EliLilly, Janssen, Johnson&Johnson, Medavante, Roche, lecture honoraria
44
from AstraZeneca, BristolMyersSquibb, EliLilly, EssexPharma, Janssen, Johnson&Johnson, Lundbeck Institute, Pfizer, SanofiAventis, and EliLilly has provided medication for a trial with SL as the primary investigator. All other authors have declared that there are no conflicts of interest in relation to the subject of this study.
References 1. Carpenter WT, Koenig JI. The evolution of drug development in schizophrenia: past issues and future opportunities. Neuropsychopharmacology 2008;33:2061–2079. 2. Leucht S, Arbter D, Engel RR, Kissling W, Davis JM. How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Mol Psychiatry 2009;14:429–447. 3. World Health Organization. International statistical Classification of Diseases and Health Related Problems. Geneva: World Health Organization; 2004. 4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). Washington DC: American Psychiatric Association; 2000. 5. Braff DL, Ryan J, Rissling AJ, Carpenter WT. Lack of use in the literature from the last 20 years supports dropping traditional schizophrenia subtypes from DSM-5 and ICD11. Schizophr Bull 2013;14:7–9. 6. Carpenter WT, Tandon R. Psychotic disorders in DSM-5: summary of changes. Asian J Psychiatr 2013;6:266–268. 7. Colonna L, Saleem P, Dondey-Nouvel L, Rein W. Longterm safety and efficacy of amisulpride in subchronic or chronic schizophrenia. Amisulpride Study Group. Int Clin Psychopharmacol 2000;15:13–22. 8. M€oller HJ, Boyer P, Fleurot O, Rein W. Improvement of acute exacerbations of schizophrenia with amisulpride: a comparison with haloperidol. PROD-ASLP Study Group. Psychopharmacology 1997;132:396–401. 9. Peuskens J, Bech P, M€oller HJ, Bale R, Fleurot O, Rein W. Amisulpride vs. risperidone in the treatment of acute exacerbations of schizophrenia. Amisulpride study group. Psychiatry Res 1999;88:107–117. 10. Puech A, Fleurot O, Rein W. Amisulpride, and atypical antipsychotic, in the treatment of acute episodes of schizophrenia: a dose-ranging study vs. haloperidol. The Amisulpride Study Group. Acta Psychiatr Scand 1998;98:65–72. 11. Sechter D, Peuskens J, Fleurot O, Rein W, Lecrubier Y. Amisulpride vs. risperidone in chronic schizophrenia: results of a 6-month double-blind study. Neuropsychopharmacology 2002;27:1071–1081. 12. Carriere P, Bonhomme D, Lemperiere T. Amisulpride has a superior benefit/risk profile to haloperidol in schizophrenia: results of a multicentre, double-blind study (the Amisulpride Study Group). Eur Psychiatry 2000;15:321–329. 13. Wetzel H, Gr€ under G, Hillert A, et al. Amisulpride versus flupentixol in Schizophrenia with predominantly positive Symtomatology – A double-blind controlled study comparing a selective D2-like antagonist to a mixed D1- /D2like antagonist. Psychopharmacology 1998;137:223–232. 14. Overall JE, Gorham DR. The brief psychiatric rating scale. Psychol Rep 1962;10:799–812. 15. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987;13:261–276. 16. American Psychiatric Association. Diagnostic and Statistical Manual for Mental Disorders, Third Revision, Revised (DSM-III-R). Washington DC: American Psychiatric Association; 1987.
Amisulpride in paranoid versus disorganized patients 17. American Psychiatric Association. Diagnostic and Statistical Manual for Mental Disorders. 4th edn. Washington, DC: American Psychiatric Association; 1994. 18. GUY W. Clinical Global Impressions ECDEU Assessment Manual for Psychopharmacology, Revised. Rockville, MD: National Institute of Mental Health, 1976:218–222. 19. Baethge C. Long-term treatment of schizoaffective disorder: review and recommendations. Pharmacopsychiatry 2003;36:45–56. 20. Pagel T, Baldessarini RJ, Franklin J, Baethge C. Heterogeneity of schizoaffective disorder compared with schizophrenia and bipolar disorder. Acta Psychiatr Scand 2013;128:238–250. 21. Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. J Clin Psychiatry 1997;58:538–546. 22. Davis JM, Chen N. The effects of olanzapine on the 5 dimensions of schizophrenia derived by factor analysis: combined results of the North American and international trials. J Clin Psychiatry 2001;62:757–771. 23. Lepping P, Sambhi RS, Whittington R, Lane S, Poole R. Clinical relevance of findings in trials of antipsychotics: systematic review. Br J Psychiatry 2011;198:341–345.
24. Schooler NR. New antipsychotic medications: strategies for evaluation and selected findings. Schizophr Res 1997;27:249–259. 25. First MB, Spitzer RL, Miriam G, Williams JBW. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition. (SCID-I/P). New York: New York Biometrics Research New York State Psychiatric Institute, 2002. 26. Sheehan DV, Lecrubier Y, Sheehan KH, et al. The MiniInternational Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998;59(Suppl 2):22–33. quiz 34–57. 27. Schennach-Wolff R, Obermeier M, Seem€uller F, et al. Evaluating depressive symptoms and their impact on outcome in schizophrenia applying the Calgary Depression Scale. Acta Psychiatr Scand 2011;123:228–238. 28. Fink M. Catatonia: a syndrome appears, disappears, and is rediscovered. Can J Psychiatry 2009;54:437–445. 29. Fink M. Rediscovering catatonia: the biography of a treatable syndrome. Acta Psychiatr Scand 2013;127(Suppl 441):1–47. 30. Fink M. Hidden in plain sight: catatonia in pediatrics. Acta Psychiatr Scand 2012;125:11–12.
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© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA PSYCHIATRICA SCANDINAVICA
Do patients with paranoid and disorganized schizophrenia respond differently to antipsychotic drugs? Corves C, Engel RR, Davis J, Leucht S. Do patients with paranoid and disorganized schizophrenia respond differently to antipsychotic drugs? Objective: The aim of this study was to compare the differential response to amisulpride in patients with paranoid versus disorganized schizophrenia. Method: We reanalyzed the original data from five different randomized drug trials comparing Brief Psychiatric Rating Scale (BPRS) scores in a database containing 427 paranoid and 296 disorganized patients with schizophrenia. Results: Both the disorganized and the paranoid group showed a substantial improvement of the BPRS total score within the first 4 weeks. In the paranoid group, mean (SD) BPRS reduction was 16.9 (14.6) (t = 24.06, df = 426, P < 0.001) and in the disorganized group 17.0 (15.9) (t = 18.49, df = 295, P < 0.001). An analysis of covariance (ANCOVA) controlling for BPRS at baseline and the influence of different trial protocols showed significant differences between diagnostic groups (F = 13.47, df = 1, P < 0.001), Cohen’s D 0.31 (CI = 0.16–0.46). Paranoid patients improved by 4.8 BPRS points more than disorganized patients (adjusted means 18.90 (CI = 17.33–20.37) for the paranoid and 14.1 (CI = 12.04 – 16.11) for the disorganized group. Conclusion: We conclude that amisulpride is effective in disorganized as well as in paranoid schizophrenia, but that symptom reduction in the disorganized subtype is less pronounced.
C. Corves1,2, R. R. Engel2,
J. Davis3, S. Leucht1
1 Department of Psychiatry and Psychotherapy, Technische Universit€at M€unchen, Munich, 2 Psychiatrische Klinik und Poliklinik, Klinikum der LMU, Munich, Germany and 3Psychiatric Institute, University of Illinois at Chicago, Chicago, IL, USA
Key words: schizophrenia; disorganized; paranoid; amisulpride; efficacy Stefan Leucht, Department of Psychiatry and Psychotherapy, Technische Universit€at M€unchen, Klinikum Rechts der Isar, Ismaningerstr. 22, 81675 Munich, Germany. E-mail: [email protected]
Accepted for publication November 6, 2013
Significant outcomes
• This •
is the first study that examines the effects of an antipsychotic in patients with paranoid vs. disorganized schizophrenia. The improvement was significantly greater in the paranoid group, when severity of illness at baseline was taken into account.
Limitations
• Diagnoses of schizophrenia subtype were not validated by SCID (Structured Clinical Interview for •
DSM) or M.I.N.I. (Mini-International Neuropsychiatric Interview), but were made based on a structured clinical interview according to the Diagnostic and Statistical Manual for Mental Disorders. There was no placebo group, but the symptom reduction was so large that it is unlikely to be simply due to the natural course.
Introduction
Antipsychotic medication is the standard treatment for patients with schizophrenia, and their success in reducing symptoms has been extensively 40
studied (1). Given the well-documented general efficacy of antipsychotics (2), it is surprising that there are no systematic studies of their efficacy on different schizophrenia subtypes, even though these may differ substantially in symptomatology.
Amisulpride in paranoid versus disorganized patients While according to ICD-10 (3) and DSM-IV (4) the undifferentiated type is by definition a mixed form and the residual subtype is characterized mainly by residing symptoms of low severity, the paranoid, the disorganized (termed hebephrenic in ICD-10), and the catatonic subtype differ substantially in symptoms (3, 4). It is unclear how well patients with different subdiagnoses respond to antipsychotics, because subgroups are generally combined in analyses of randomized controlled trials. In a MEDLINE search (Medical subject headings search terms: schizophrenia, hebephrenia, disorganized, catatonia, subtype/subcategory, date: 1966–2013), we did not find any primary or post hoc analyses on the different subgroups [also see (5)]. One reason for this may be that analyses of subgroups would usually be underpowered, as the sample size estimations of single trials are made for pooled analyses. Although the subtypes are defined based on convention and only partly on empirical evidence and might not reflect etiologically and neurobiological distinct pathologies, it is common clinical practice to differentiate them. DSM-5 has abandoned the schizophrenia subtypes (6), and experts working on ICD-11 need to make a decision whether they want to follow this path. It is therefore crucial to know whether these subdiagnoses have implications for treatment efficacy. Aims of the study
The aim of this study was to provide an analysis comparing the efficacy of a second-generation
antipsychotic drug on paranoid and disorganized schizophrenia in a pooled database of registrational amisulpride studies in acute schizophrenia. As described above, symptoms between the disorganized subtype and the paranoid subtype differ but overlap. As efficacy has already been demonstrated for the paranoid subtype, we would expect patients with disorganized schizophrenia to respond to treatment. This should be reflected in a significant reduction in symptom severity as compared with baseline in the disorganized group.
Material and methods Sample
We post hoc reanalyzed data from five trials on amisulpride comprising patients diagnosed with disorganized as well as paranoid schizophrenia [Colonna et al. (7); M€ oller et al. (8); Peuskens et al. (9); Puech et al. (10); Sechter et al. (11)], see Table 1. Two other amisulpride trials were available [Carriere et al. (12); Wetzel et al. (13)] but did not include a single patient of the disorganized subtype and were therefore disregarded. All studies were randomized, and apart from one open study (7), all were double blind and used a parallel design. The studies were mainly conducted for registrational purposes and compared amisulpride with either haloperidol (7, 8, 10) or with risperidone (9, 11). Study duration ranged between 4 weeks and 1 year (7). Two studies (7, 11) used a flexible-dose
Table 1. Characteristics of the included studies Dose (mg/day) of amisulpride
Study
n
par
dis
M€oller et al. (8)
75
32
43
6
800*
Puech et al. (10)
139
48
91
4
100‡, 400, 800 or 1200
Colonna et al. (7)
280
160
120
51
Peuskens et al. (9)
97
71
26
8
Sechter et al. (11)
132
116
16
26
Weeks
200–1200 (flexible dose, mean 614) 800
400–1000 (flexible dose, mean 655)
Selected patient characteristics In-patients with paranoid, disorganized, or undifferentiated schizophrenia, DSM-III-R, BPRS psychotic subscore† ≥12 and at least two BPRS psychosis items ≥4 In-patients with acute exacerbations of paranoid, disorganized, or undifferentiated schizophrenia, DSM-III-R, BPRS psychotic subscore ≥12 and at least two BPRS psychosis items ≥4 In- or out-patients with acute exacerbations of paranoid, disorganized, or undifferentiated schizophrenia, DSM-III-R, at least two BPRS psychosis items ≥4 In- or out-patients with paranoid, disorganized or undifferentiated schizophrenia, DSM-IV, BPRS total score ≥36, BPRS psychotic subscore ≥12 and at least two BPRS psychosis items ≥4 In- or outpatients with chronic (at least 2 years) paranoid, disorganized, undifferentiated, or residual schizophrenia, DSM-IV, PANSS ≥60 ≤ 120, 0.05). Results of univariate analyses
Unpaired t-tests and chi-square tests showed statistically significant differences between groups for trial [v2(4) = 96.7, P < 0.001] and BPRS at baseline (t = 9.85, df = 721, P < 0.001), with a mean of 53.8 (10.7) in the paranoid group compared with 61.8 (10.9) in the disorganized group. There was no significant difference in terms of gender (P = 0.53), duration of illness below or above 2 years (P = 0.23), duration of illness in days (P = 0.86), age (P = 0.07), or amisulpride dose (P = 0.15). Comparison of subtypes Week four
The ANCOVA yielded significant main effects for subtype (F = 13.47, df = 1, P < 0.001), demon-
Amisulpride in paranoid versus disorganized patients strating a significant difference between groups and a greater symptom reduction in the paranoid (adjusted means 18.9 (CI = 17.3–20.4) than in the disorganized group 14.1 (CI = 12.0–16.1), Cohen’s D 0.31 (CI = 0.16–0.46). In addition, the ANCOVA yielded significant effects on baseline severity (F = 122.13, df = 1, P < 0.001) and trial (F = 7.38, df = 4, P < 0.001). The interaction between subtype and trial was not significant. Study endpoint
This ANCOVA showed a similar pattern. There was a main effect for subtype [F = 8.30, df = 1, P < 0.005, Cohen’s d = 0.25 (CI = 0.11–0.40)], with estimated adjusted mean BPRS reduction of 20.3 (CI = 18.6–22.0) in the paranoid and 16.1 (CI = 13.8–18.4) in the disorganized group. Again, there were significant effects of severity at baseline (F = 115.54, df = 1, P < 0.001), but not of trial (f = 2.02, df = 4, P = 0.90). The interaction between subtype and trial was not significant. Correlation of symptom reduction and baseline severity
There was an obvious discrepancy between the virtually identical mean raw symptom reduction in both groups [16.9 BPRS points (14.6) in the paranoid group and 17.0 (15.9) in the disorganized group, difference non-significant] and the ANCOVA results (significant difference (F = 13.47, df = 1, P < 0.001) between paranoid [adjusted means 18.90 (CI = 17.33–20.37) and the disorganized group 14.1 (CI = 12.0–16.1), Cohen’s D 0.31 (CI = 0.16–0.46), as described above]. To find out whether this was associated with the significantly higher baseline severity in the disorganized group (see above), we correlated baseline severity with symptom reduction and found a positive correlation (N = 723, r = 0.38, P < 0.001). As the disorganized group had a higher degree of severity at baseline (see above), this suggests that the stronger reduction in symptoms in the paranoid group was not an artifact of unequal baseline scores. Discussion
The main results of this study are as follows both the paranoid and the disorganized subgroup experienced a robust reduction in symptoms. However, the reduction in symptoms was larger in the paranoid group as is indicated by an ANCOVA, taking trial and baseline differences into account. Generally, a higher degree of severity at baseline was associated with significantly greater symptom reduction, but although the disorganized partici-
pants were significantly more ill at baseline, they did not show higher reduction scores. The efficacy of antipsychotic drugs for the different subgroups of schizophrenia has been studied surprisingly little. There are very few randomized controlled trials that examined subgroups of patients with schizoaffective disorder [a review by Baethge (2003) (19) found only one], a heterogeneous disorder (20) that is considered to be a different diagnostic group rather than a schizophrenia subtype. Other studies analyzed the effects of medication on empirically derived symptom clusters: Marder et al. (21), for instance, derived symptom dimensions using factor analyses and found that risperidone’s superiority over haloperidol was significantly greater for some dimensions (negative symptoms, hostility/excitement, anxiety/depression) than for others (positive symptoms, disorganized thought), suggesting that risperidone and other serotonin/dopamine antagonists are in effect qualitatively different from haloperidol. An analysis of pivotal olanzapine studies (22) identified different symptom dimensions by factor analyses and found that olanzapine was better than haloperidol to an equal degree in all of them. These studies were quite different from ours, because they examined differences in subgroups of symptoms not patients. None of them examined the effects on the DSM/ICD defined subgroups of schizophrenia, which is crucial information for the clinician. The 4.8-point difference in BPRS total score found in the ANCOVA is relatively small as it corresponds to a 0.5-point difference on the CGI where 1 point reflects minimal improvement. On the other hand, a meta-analysis (38 studies, n = 7323) found an only nine BPRS points difference between second-generation antipsychotics and placebo (2). The 4.8 points difference also appears larger in the light of a review by Lepping et al., 2011 (23), which found that second-generation antipsychotics reduced the BPRS baseline score by 15.0 7.2 points. Various limitations must be considered: First, our data set consisted in a mix of fixeddose and flexible-dose studies. Generally, a fixeddose design could be associated with a less favorable outcome, as patients do not necessarily obtain the optimal dose balancing symptom reduction and adverse effects. Consequently, dropout rates may be higher and symptom reduction lower. It has been argued that flexible-dose studies better approximate clinical practice and therefore also the treatment benefit that can be expected in a clinical setting (24). Conversely, it is an advantage of the fixed-dose studies in our database that they 43
Corves et al. kept the factor dose constant, which could have interacted with the schizophrenia subtype. Second, the diagnosis of the participants in the included RCTs were not validated by Structured Clinical Interview for DSM (SCID) (25) or Mini-International Neuropsychiatric Interview (M.I.N.I)(26), but with a structured clinical interview according to DSM-III-R(IV). On the other hand, there is no reason to assume that the accuracy of diagnosis is particularly low in these studies as in general practice diagnosis is also made in the absence of a SCID. Third, only a placebo group could prove that amisulpride is efficacious for both paranoid and disorganized patients. But the BPRS reduction from baseline was so large (17 points) that this should not be a major concern. For example, in the review by Lepping et al., 2011 placebo reduced the BPRS by 2.3 3.7 points in similar studies. Fourth, the current analysis compared only disorganized and paranoid schizophrenia, but not catatonic schizophrenia. However, this subtype is very rare in clinical trials [only 1.7% in our database, also see, e.g., (27)], and it has been repeatedly argued that catatonia constitutes a distinct syndrome separate from schizophrenia (28–30). In DSM-5, the strong relation to schizophrenia has been loosened together with the deletion of the subtypes. Although not a separate diagnosis, catatonia is included as a specifier, which can be applied not only to schizophrenia but also to several other psychiatric diagnoses. Finally, an important limitation of this study is its focus on amisulpride. Other antipsychotic agents than amisulpride need to be examined to enhance generalizability. Currently, the question to what extent the difference in response between the two diagnostic groups depends on a specific antipsychotic agent remains to be examined. In conclusion, this study demonstrates that amisulpride is effective for patients diagnosed with paranoid and disorganized schizophrenia, but it also suggests that the effects on the paranoid subtype are stronger. These results have an impact on the decision whether ICD-11 should follow the abolishment of diagnostic subcategories of schizophrenia by DSM-5(6). Acknowledgements We would like to thank SanofiAventis for providing the raw data of the original studies.
Declaration of interest Stefan Leucht has received honoraria for consulting/advisory boards from Alkermes, BristolMyersSquibb, EliLilly, Janssen, Johnson&Johnson, Medavante, Roche, lecture honoraria
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from AstraZeneca, BristolMyersSquibb, EliLilly, EssexPharma, Janssen, Johnson&Johnson, Lundbeck Institute, Pfizer, SanofiAventis, and EliLilly has provided medication for a trial with SL as the primary investigator. All other authors have declared that there are no conflicts of interest in relation to the subject of this study.
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